Baclofen as a therapeutic option for gastroesophageal reflux disease: A systematic review of clinical trials

Background The main components of gastroesophageal reflux disease (GERD) management include a combination of medications and lifestyle modifications; Nevertheless, based on the severity of symptoms and their response to medications, other treatments could be considered. Baclofen has been demonstrated in studies to relieve GERD symptoms. The current study aimed to precisely address the effects of baclofen on the treatment of GERD and its characteristics. Methods A systematic search was carried out in Pubmed/Medline, Cochrane CENTRAL, Scopus, Google Scholar, Web of Science, and clinicaltrials.gov up to December 10, 2021. The search terms included baclofen, GABA agonists, GERD, and reflux. Results We selected 26 papers that matched the inclusion criteria after examining 727 records. Studies were classified into four categories based on the study population and reported outcomes: (1) adults, (2) children, (3) patients with gastroesophageal reflux-induced chronic cough, (4) hiatal hernia patients. The results revealed that baclofen can significantly improve reflux symptoms and pH-monitoring and manometry findings to different degrees in all four mentioned categories; although its effect on pH-monitoring parameters seems less significant than the other parameters. Mild neurological and mental status deterioration were the most reported side effects. However, side effects occurred in a portion of less than 5% of short-term users and nearly 20% of long-term users. Conclusion In PPI-resistant patients, a trial of adding baclofen to the PPI may be helpful. Baclofen therapies may be more beneficial for symptomatic GERD patients who also report concurrent conditions including alcohol use disorder, non-acid reflux, or obesity. Systematic review registration https://clinicaltrials.gov/.


Introduction
Gastroesophageal reflux disease (GERD) is a clinical condition caused by the chronic retrograde reflux of acidic contents of the stomach into the esophagus with discomforting symptoms or complications or both (1). Gastroesophageal reflux (GER) is a physiological condition during infancy and childhood and may not require treatment. In children, GERD is the symptomatic reflux of gastric contents into the esophagus and should be treated according to the severity of symptoms (2,3). Global surveys in 2017 estimated an 18.1% increase in the total prevalence of GERD cases and a 67.1% increase in the years lived with disability (YLD) compared to 1990 (4). These findings suggest GERD as a public health concern with a considerable socioeconomic burden in the near future.
Diagnosis of GERD is based on clinical symptoms (heartburn, regurgitation, and non-cardiac chest pain) and response to empiric proton pump inhibitors (PPIs). Nonetheless, studies have shown limitations of non-objective diagnosis; as a result, diagnostic evaluation such as upper endoscopy is recommended based on the clinical setting, especially in patients with red flags like dysphagia (5).
The main components of GERD management are lifestyle modification and PPIs. Nevertheless, based on the severity of symptoms and their response to PPIs, H2blockers, baclofen, antacids, sucralfate, prokinetic agents, and invasive anti-reflux procedures (such as surgeries, sphincter augmentation, and endoscopic therapy) are considered in combination with other treatments or as the replacement therapy for patients. Consideration is required based on efficacy and tolerability profile of each treatment option (5)(6)(7).
The pathophysiology of GERD is multifactorial and is explained by natural anti-reflux barrier. Studies suggest following mechanisms for GERD: the hypotonic lower esophageal sphincter (LES), hiatal hernia, Gubaroff valve failure, and thoraco-abdominal pressure (8,9). Also, studies have shown that baclofen has been highly beneficial in the treatment of refractory GERD. Baclofen is an FDA-approved agonist of the gamma-aminobutyric acid (GABA) receptor, which is generally used for the relaxation of pathologic spasms originating from the central nervous system (CNS). Its mechanism of action on GERD is by inhibition of LES relaxation induced via vasovagal reflexes. Baclofen inhibits these reflexes through GABA B receptor activation (10,11).
Although previous studies proved effectiveness of baclofen on GERD (12), to the date, there are no systematic reviews regarding outcomes and side effects in different patient (grouped by: age, and comorbidities); A systematic review in that regard might resolve probable hesitancies in prescribing baclofen. Therefore, we will conduct this systematic review, aiming to facilitate informed decisions in managing GERD using baclofen. To achieve this goal we will review efficacy, side effects, and response predictors in different patients grouped by: age (adult vs. pediatrics), comorbidities (hiatal hernia and GERD-related chronic cough), and some other factors.

Materials and methods
This study was conducted and reported according to the Preferred Reported Items for Systematic Reviews and Meta-Analysis (PRISMA) statement (13). countries: United States (n = 6), China (n = 4), Iran (n = 3), Australia, Belgium, Italy, Sweden (n = 2, for each one), Switzerland, the Netherlands, Mexico, Japan, and Germany (n = 1, for each one) ( Table 1). Two of the studies had two separate parts (15,16), so we looked at these parts separately and overviewed 28 studies as a whole. All studies assessed baclofen efficacy based on clinical status, pH monitoring, or manometry findings. Additionally, in most trials, the safety of treatment was evaluated by the occurrence of adverse events or side effects.

Quality of included studies
Based on the NIH checklists for controlled intervention and before-after (pre-post) studies with no control group, the included studies had a low risk of bias (Supplementary Tables 2, 3).

Patient characteristics
Except for one study that did not report the number of patients (17), the remaining 27 trials included 785 patients who got baclofen and 358 who received control medication. The baclofen groups included individuals aged 7.1 months (infants) to 58 years (adults). The most frequently utilized methods for diagnosing GERD were, in order, history, pH monitoring, manometry, and endoscopy ( Table 2).

Intervention characteristics
In twenty-two studies, the treatment regimen consisted only of baclofen, whereas in the six remaining studies, the treatment regimen consisted of baclofen and a PPI (18)(19)(20)(21)(22)(23). The majority of studies used baclofen for at least 1 week; however, some used shorter treatment periods to investigate baclofen's acute effects. In all studies, treatments were administered orally, except one that also administered enteric baclofen (24) (Table 3).

Safety and side effects
Among 28 studies, four studies did not investigate treatment side effects (17,(25)(26)(27). No treatment-related severe adverse events were observed in the remaining 24 studies. The adverse effects noted were somnolence among 14.2% of participants, dizziness (10.0%), fatigue (4.9%), nausea (1.6%), gastrointestinal symptoms (0.9%), headache (0.7%), anxiety (0.2%), and a slight reduction in muscular tone (0.2%). The most frequently reported adverse effects were neurological and mental status deterioration (particularly dizziness and somnolence). However, some of these events were not induced by baclofen; rather, they were caused by the other underlying comorbidities. The side effects occurred in a portion of less than 5% of short-term users (less than 4 weeks) and nearly 20% of long-term users (more than 4 weeks), and also occurred during placebo therapy in certain studies. Baclofen had no adverse effects in seven studies, and was well tolerated (11,16,18,21,(28)(29)(30) ( Table 4).

Efficacy
Studies were classified into four categories based on the study population and reported outcomes: (1) adults, (2) children, (3) patients with gastroesophageal reflux-induced chronic cough, and (4) hiatal hernia patients.

Outcomes in adults
This category contained seventeen studies. These publications evaluated baclofen's efficacy using changes in clinical status, acid reflux time, TLESR incidence, GER incidence, LES pressure, and some other parameters.
Eleven trials reported changes in clinical status. Baclofen significantly improved clinical symptoms in seven studies. However, Bajbouj et al. (19) and Zhang et al. (11) discovered no significant improvement following baclofen treatment. According to Abbasinazari et al. (18) baclofen alleviated esophageal symptoms (heartburn and regurgitation) but had no significant effect on extra-esophageal symptoms (chest pain and hoarseness). Baclofen reduced belching with no effect on other reflux symptoms in Cange et al.'s (31) trial.
Changes in acid reflux time were documented in eleven studies. Baclofen significantly decreased acid reflux time in five studies. However, four studies found that baclofen has no significant effect on acid reflux time (11,15,19,20). Orr et al. (30) reported that baclofen reduced recumbent acid contact time by 50% compared to placebo, although the difference was not statistically significant. In Curcic et al.'s (28) study, baclofen increased reflux duration by a small but significant degree.
Four studies reported changes in TLESR incidence. All of them mentioned that baclofen has a significant reducing effect on TLESR incidence (11,(32)(33)(34).
Thirteen studies reported changes in GER incidence. All of them declared baclofen had a significant effect on reducing GER incidence, except for two studies: (a) Koek et al. (20) reported that after adding baclofen, the number of acid reflux episodes remained unchanged, but the number of duodenal reflux episodes and the number of duodenal reflux episodes lasting longer than 5 min decreased significantly. (b) Bajbouj et al. (19) observed no significant changes in reflux episodes, before and after adding baclofen. Additionally, two trials examined the effect of body posture on efficacy of baclofen (15,25). Both of them suggested that baclofen decreased reflux episodes in the upright position significantly, while reflux episodes in the supine position did not change significantly.
Six studies investigated changes in LES pressure. Baclofen significantly elevated LES pressure in four studies (11,28,32,33). Cossentino et al. (25) and van Herwaarden et al. (34) on the other hand, found no difference in LES pressure between the baclofen and placebo groups. All outcomes are present in more detail in Table 5.

Outcomes in children
Six studies were included in this category. The mean age of the participants ranged between 7.1 months and 10.0 years.
Four studies reported changes in clinical status. All of them confirmed baclofen's significant efficacy in the improvement of clinical status by symptom remission, weight gain, or reduction in crying and restlessness.
Three studies evaluated the efficacy of baclofen in children using invasive GI procedures (pH monitoring or esophageal Flow chart of study selection for inclusion in the systematic review and meta-analysis. manometry). Omari et al. (35) and Dibner (17) found that children receiving baclofen had considerably lower TLESR and acid GER compared to children receiving a placebo. In Kawai et al.'s (24) study, the total number of acid reflux events was reduced significantly during the postprandial and entire 24-h periods. However, they found no significant changes in total acid exposure time, the percentage of time with esophageal pH < 4 and the duration of the longest acid reflux resulting from baclofen (24) ( Table 6).

Outcomes in patients with GERC
In this category, four studies were included. Cough period ranged from 12.6 to 36 months on average. The daytime cough symptom score was greater (3,4) than the night time cough symptom score (1,2). Overall, baclofen was effective in treating GERC in 122 of 214 (57.0%) individuals. Outcomes are available in more detail in Table 7.

Outcomes in patients with HH
Three studies were included in this category because they featured a subgroup of patients with HH. Cange et al. (31) reported a significant reduction in acid reflux time and reflux episodes after receiving baclofen, compared to placebo. Beaumont et al. (15) found no significant changes in total acid exposure time and the percentage of time with pH < 4 in patients with HH after administration of baclofen and placebo. However, they observed  that baclofen reduced the total number of reflux episodes compared to placebo. In addition, they made a comparison between patients with and without HH and found: (I) patients with a large HH did not show a significantly more proximal reflux compared to patients without HH. No correlation was found between the size of the HH and the proximal extent of the reflux (r = 0.1; P = 0.75); (II).   The total number of reflux episodes of placebo was significantly higher in patients with HH and remained significantly higher compared to in patients without HH (P < 0.05). No correlation (r = 0.01; P = 0.95) was found between the size of the HH and the number of acid reflux episodes (15). In Scarpellini et al.'s (33) study, preprandial LES pressures following baclofen were significantly lower in patients with HH compared to those without HH (P < 0.05), and did not change significantly in the postprandial period ( Table 8). Table 9 summarizes the evidence from the included studies regarding the feasibility of using baclofen in the treatment of GERD.

Summary of the main results
We conducted this study to review the effects of baclofen on the treatment of GERD along with its advantages and disadvantages. Most included studies we reviewed diagnosed GERD based on clinical presentation and only a few diagnosed on pH-monitoring results. The results showed that baclofen is a relatively safe choice that may significantly improve reflux symptoms and pHmonitoring and manometry findings, although its effect on pHmonitoring parameters seems less significant than the other parameters. Baclofen showed effective to different degrees in all of four assessed categories (including adults, children, patients with GERC, and patients with HH).

References
Treatment side effects The mechanisms, safety, and efficacy of baclofen in the GERD management will be discussed in the following sections.

Mechanisms
Baclofen is a GABA agonist that works primarily in the spinal cord by binding to GABA B receptors and inhibits the release of substance P and excitatory neurotransmitters; so, baclofen alleviates muscle spasms and discomfort (36). Although the spinal cord is the principal site of action for baclofen, its receptors are also found in the brain. Studies suggest that baclofen interacts with serotonin, dopamine, and other neurotransmitters, an off-label treatment for post-traumatic stress disorder and anxiety (37).
However, how does baclofen work to treat gastroesophageal reflux? The molecular and neural mechanisms of action of baclofen in reflux disease are still unclear. The vasovagal reflex relaxes the LES as food enters the stomach, but predisposes to acid and food reflux to occur. As a result, the TLESR is the most likely cause for the gastroesophageal reflux disease. Number of neurotransmitters play a role in this reflex, but GABA B receptor agonists have received the most attention for drug intervention. A low basal pressure of the LES is another proposed mechanism for reflux disease (38,39). All included clinical trials reported the significant effect of baclofen on TLESRs and LES pressure, except for Cossentino et al. (25) and van Herwaarden et al. (34) who found no significant change in LES pressure between the baclofen and placebo groups. They prescribed baclofen for a period of 2 weeks and 1 day, respectively. Their result does not seem to be attributable to the period of baclofen administration, since there are some studies reporting the efficacy of baclofen on LES pressure during the same administration period (11,28,32,33). The intensity and frequency of symptoms were significantly improved in patients after receiving baclofen, while in the placebo group the total symptom scores was not changed. The number of antacid tablets consumed per week was 7 before placebo, 8 during placebo (NS), 8 before baclofen, and 2 during baclofen (p < 0.01).
The percent time pH < 4 was significantly decreased after the treatment with baclofen compared to the values reported at the beginning of the treatment (-53.45%). The percent time with pH < 4 in GERD patients treated with placebo was not significantly changed (p = NS)

NR
The number of reflux episodes was significantly decreased after the treatment with baclofen compared to the values reported at the beginning of the treatment (-76.36%). The median number of reflux episodes in GERD patients receiving placebo was not significantly changed (p = NS)

NR
The number of reflux episodes longer than 5 min was assessed in five patients treated with baclofen and in three patients treated with placebo. In baclofen group, a significant reduction was noted (p < 0.002) while no change was observed in placebo group (p = NS).

NR
The total acid exposure time and the percentage of time pH < 4 after baclofen treatment, both not significantly changed compared with the placebo. No significant changes in the percentage of time with pH < 4 were noted for the upright, postprandial, and supine periods compared with placebo. Acid clearance time was not changed significantly after baclofen (p = NS).

NR
After Baclofen, the total amount of reflux episodes was significantly reduced (P < 0.01). Reflux in the upright position and postprandial reflux were significantly decreased [(P < 0.02) and (P < 0.02), respectively]. Number of reflux episodes in the supine position was not significantly changed after treatment baclofen. The number of acid reflux episodes was reduced by 36.6%, however this change was not statistically significant compared to placebo. Bolus clearance was not affected by baclofen (p = NS)

NR
The total number of reflux episodes extending to the most proximal impedance electrodes was significantly reduced after treatment with baclofen (P < 0.05) The total amount of belching was significantly decreased (P < 0.01), but no effect was observed on heartburn or other symptoms associated with GERD.

Frontiers in Medicine
A significant reduction was observed in the fraction of time pH < 4 during the first 4 h after dosing with baclofen (P = 0.0019), postprandially (P = 0.0083) and for the whole 12-h period (P < 0.039). However, during the 4-8 and 8-12 h periods, no significant reduction was noted.
NR After baclofen, a significant reduction in the number of acid reflux episodes, both during the first 4 h after dosing (48%) and during the total 0-12 h recording period (P < 0.0001) was recorded.

NR
Baclofen had no significant effect on esophageal clearance.
Significant improvement in 24-h pH score (P = 0.020) after treatment with baclofen was noted. NR Baclofen significantly reduced the acid reflux time (P = 0.029). In contrast, baclofen had no effect on the mean duration of reflux episodes (P = NS).
The incidence of TLESR was significantly reduced after the treatment with baclofen compared to placebo (P < 0.0001); However, baclofen had no effect on the percentage of TLESR  The proximal extent of acid pockets detected postprandially was not affected by baclofen or placebo (P = NS).
Zhang et al. (11) No overall significant differences in changes in symptom scores after baclofen administration compared to placebo were noted.
Although reflux episodes were significantly reduced, esophageal acid exposure was not significantly affected by baclofen. The duration of time that esophageal pH was <4 was not changed during baclofen compared to that during placebo (p = NS).  Koek et al. (20) After adding baclofen to the treatment, overall symptom severity was significantly reduced (p < 0.01). The severity of heartburn, odynophagia, and choking was significantly reduced (p < 0.05) and a borderline reduction in the severity of throatache was noted (p = 0.07).

Frontiers in Medicine
Under combination therapy with omeprazole 20 mg BD and baclofen 20 mg TDS, esophageal acid exposure was unchanged but distal esophageal exposure duodenal reflux was significantly reduced (p < 0.05).

NR
The number of acid reflux episodes was unchanged after addition of baclofen. The number of duodenal reflux episodes and the number of duodenal reflux episodes lasting longer than 5 min were significantly reduced. Duodenal reflux exposure during treatment with baclofen was decreased both in the upright and supine positions.

NR NR
Bajbouj et al.
None of the patients experienced a significant resolution of symptoms after adding baclofen to the treatment.
No significant changes were noted before and after adding baclofen.  Children receiving baclofen had significantly less TLESR and acid GER in the test duration than in the control duration and for the placebo group, no differences were detected. Children receiving baclofen had faster gastric emptying and a higher frequency of normal gastric emptying than those who received the placebo.

NR
Omari et al. (35) 10.0 (9.1/11.0) years NR In the control period, the average number of acid GER episodes and the proportion of TLESR-associated acid GER episodes in the placebo group were significantly lower than in the baclofen group. Children receiving baclofen 1 h before the second drink, recorded significantly fewer TLESRs and acid GER episodes during the test in comparison with the control period. For children receiving the placebo, no significant differences between the test and control periods for the frequency of TLESRs and reflux were recorded.
6.1 years 66% of patients showed a significant reduction in clinical symptoms at their first follow-up visit. Baclofen was stopped in the remaining 34% of patients because of either no response (28%) or adverse events (6%). A total of 27 patients continued treatment and were assessed for long-term response. Of those 81% had a sustained response to baclofen at 12 months, whereas 19% lost response.
7.1 months The average weight gain of patients was significantly increased (p < 0.0001). Crying and instability were significantly decreased (p < 0.0001). Vomiting was significantly decreased (p < 0.0001). The feeding frequency was significantly increased (p < 0.001).
There are still many questions about the mechanism of baclofen in GERD. Although the manometry findings confirm the effect of baclofen on the LES, baclofen has been less effective on pHmonitoring findings. Unlike PPIs, baclofen has no known effect on gastric acid secretion, but theoretically, it may reduce acid exposure time secondary to increased LES pressure. However, most of the studies reported no significant improvement in acid exposure time with baclofen. Furthermore, in some of these studies, despite no significant reduction in acid exposure time, GERD symptoms were significantly improved. This can suggest other mechanisms rather than the effect on the LES; for example, baclofen may have a role in suppressing esophageal sensory neurons, as a result, despite the reflux of the acid, patient feels no heartburn. Taken together, it seems that the increased LES pressure cannot be the only mechanism of action of baclofen in GERD; more studies are needed in this field.

Safety and side effects
One of the most critical considerations in any treatment is the patient's safety. Baclofen's side effects have caused hesitancies in prescribing for the treatment of GERD.
As previously mentioned, baclofen is a GABA B agonist which justifies its side effects by this mechanism. CNS side effects may include dizziness, drowsiness, confusion, sedation, asthenia, and nausea. These side effects are dose-dependent and related to the pharmacologic action of binding to the presynaptic GABA B receptors within the brain stem, dorsal horn of the spinal cord, and other CNS parts while reducing the release of excitatory neurotransmitters. Taking oral doses of more than 60 mg per day and severe renal impairment (eGFR less than 30 ml/minute/1.73 m 2 ) are the major predictors for CNS side effects. Patients who are concurrently taking other CNS depressants >3 cm During baclofen, the total acid exposure time and the percentage of time esophageal pH < 4, both showed no significant difference compared with the placebo (p = NS). During baclofen, no significant changes in the percentage of time with pH < 4 were observed for the upright, postprandial and supine period compared with the placebo. Baclofen had no significant effect on acid clearance time.
A significant reduction in the total amount of reflux episodes was recorded (P = 0.003, corresponding with a reduction of 43.3%), but the number of acid reflux episodes had no significant reduction by baclofen. Reflux in the upright position was significantly lower (P = 0.003), but reflux in the supine position showed no significant reduction by baclofen. Baclofen significantly reduced the amount of mixed (P = 0.003) and pure liquid (P < 0.02) reflux episodes. In patients with a verified hiatus hernia (n = 13), a significant reduction was found in the number of reflux episodes for the whole registration time (P < 0.0002) as well as for each 4-h period (P < 0.05).
NR Scarpellini et al.
>2 cm NR NR Preprandial LES pressures after baclofen were significantly reduced in patients with HH compared with those without HH (P < 0.05), and had no significant change in the postprandial period.
(for example, benzodiazepines or opioids) are more susceptible to these side effects (40,41). As expected, these side effects were also observed in the clinical trials. These side effects were well explained both by the agonistic effects of baclofen on GABA B receptors in the central and peripheral nervous systems and the normal postprandial symptoms of GERD. The duration of the treatment and other factors may have an impact on its safety. We review that in short -term use the overall adverse effects of baclofen in GERD patients are negligible, yet in long-term use side effects are more prominent. However, Sobhani Shahmirzadi et al. (21) and Khodad et al. (29) administered baclofen for a period of 1 month and 3 months, respectively; and no significant adverse event was observed despite long-term use of baclofen.
Li et al. (12) conducted a meta-analysis of nine RCTs to examine the safety of baclofen in reflux therapy. Baclofen-and placebotreated participants did not have a statistically significant difference in the frequency of overall adverse events (OR = 1.62; 95% CI: 1.03, 2.54; P = 0.04). Neurological/psychiatric symptoms were the most reported side effects. All reported adverse events were mild to moderate in intensity (12).
Some clinicians administer low dose baclofen and increment the dosage as a precaution against baclofen adverse effects. This approach was utilized in six of our trials (15,16,19,20,25,42). However, results are inconclusive due to lack of studies comparing high-dose baclofen at the beginning of treatment with the incremental dosing mentioned above in adverse effects.
This review concludes an acceptable safety and tolerability profile for baclofen in GERD, yet Caution should be taken in the long-term use of baclofen, as 20% of long-term users experienced neurological and mental side effects. We noted that some trials did not report side effects, and some had restricted criteria toward side effects; therefore, side effects might not be reported in these studies. Furthermore, the populations of the included studies were heterogeneous. Thus, we recommend that cautions should be considered when administering baclofen to susceptible populations. In general, to limit the risk of baclofen side effects, we recommend: (i) starting with a low dose and gradually increasing it; (ii) prescribing no more than 60 mg of baclofen per day; and (iii) obtaining a comprehensive history of the patient, including comorbidities, medications (particularly CNS depressants) and a previous history of dizziness, somnolence and other baclofen side effects.

Efficacy
In our included trials, the efficacy of baclofen was evaluated through changes in clinical status, acid reflux time, TLESR incidence, GER incidence, LES pressure, and several other factors. Due to heterogeneity of the included studies, a meta-analysis of the data was not possible. Nonetheless, the effects of baclofen on GERD from the results are noticeable. Li et al. (12) conducted a meta-analysis on nine RCTs to determine the efficacy of baclofen on reflux statistically (eight studies administered baclofen in GERD patients and one administered baclofen in normal healthy subjects). The results revealed a statistically significant difference between baclofen-treated and placebo-treated subjects in reduction of GER incidence [standardized mean difference (SMD): −0.65; 95% CI: −0.94, −0.36; P = 0.00001], acid reflux time (SMD: −1.14; 95% CI: −1.72, −0.56; P = 00001) and TLESR incidence (SMD: −3.56; 95% CI: −4.30, −3.00; P < 0.00001) (12).
Baclofen may benefit a diverse population including: adults, infants with refractory regurgitation, neurologically impaired children with GERD, patients with GERC, and patients with hiatal hernia may benefit from baclofen. Of the twenty-six included, only Bajbouj et al. (19) and Zhu et al. (42) advised against using baclofen for the treatment of reflux disease.
The study by Bajbouj et al. (19) involved seven patients with GERD who did not respond to PPI. They added 15 mg of baclofen to the 80 mg of esomeprazole daily, which was increased to 60 mg after 1 month. They maintained this regimen for a period of 2 months. They found no significant change in patients' clinical status, acid reflux time and GER incidence after 3 months of treatment. Also, two patients discontinued the study because of drowsiness. Therefore, Bajbouj et al. (19) recommended against the use of baclofen in patients who did not respond to PPI (19). However, in all other studies, baclofen was significantly more effective than placebo in treating GERD patients who did not respond to PPI; we cannot independently explain Bajbouj (42) recommended against using baclofen because of its unsatisfactory efficacy and side effects. They discovered that LES pressure with a cut-off point of 11 mmHg (with a sensitivity of 83.1% and a specificity of 79.1%) and LES length with a cut-off point of 2.35 cm (with a sensitivity of 81.6% and a specificity of 72.1%) are the independent predictors of baclofen efficacy in reflux disease (42). Although the population of the study was limited to patients with refractory GERC, considering the mechanism of baclofen on GERD, it may be possible to use these cut-off points for all patients with refractory GERD; but more studies are needed to determine these cut-offs. However, using manometry to assess response to baclofen is impractical, as it is used in a limited portion of GERD patients.
Is baclofen a proper choice in patients with GERC? 64% of individuals in this category were the patients of Zhu et al.'s (42) study. The issue that is remarkable about their study is that they prescribed baclofen as monotherapy without PPI. 52.2% of patients were treated with baclofen and 86.3% of baclofen non-responders were treated with double dose of PPI (42). On the other hand, Xu et al.'s (23) reported that adding baclofen to the PPI was effective in cough resolution of 66.7% of patients with GERC who failed to response high-dose PPI and H2blocker. On the whole, the heterogeneity of the studies in this category prevents us from making a correct judgment, and it seems that baclofen lacks the potency for standard clinical use in patients with GERC, apart from the fact that the risk of side effects is also higher in these patients due to the long-term use.
Does HH reduce the efficacy of baclofen during PPI addon therapy? Beamount et al. (15) studied 27 GERD patients, including 16 patients without HH and 11 without a large HH. The total number of reflux episodes decreased by 36% in patients without HH and 43% in patients with HH, but the number of acid reflux episodes and total acid exposure time did not change. They reported that baclofen may also be effective in patients with a large HH but findings are not satisfactory (15). Suggested algorithm for administration of baclofen for refractory reflux disease. AUD, alcohol use disorder; EGD, esophagogastroduodenoscopy; GERD, gastroesophageal reflux disease; HREM, high resolution esophageal manometry; LESL, lower esophageal sphincter length; LESP, lower esophageal sphincter pressure; PPI, proton pump inhibitor. *Means to pay attention to the issues that are listed in red rectangle.
Is baclofen effective as a stand-alone treatment for GERD? Twenty-two studies used baclofen as monotherapy and six used it as a combination therapy with PPI. Baclofen improved symptoms in both treatment groups significantly, but due to the heterogeneity of studies, it is impossible to compare these two groups. Despite the fact that baclofen monotherapy is effective in treating GERD, it is not recommended to use it as the first-line treatment without PPI; especially for long-term use, in which case its side effects are more pronounced. We recommend that, if high-dose PPI treatment fails to improve GERD, baclofen can be added to PPI to benefit the synergistic effects. In PPI-resistant patients, baclofen could be used as a replacement for prokinetics such as domperidone; particularly in patients who have heart diseases, as prokinetics prolong the QT interval and increase the risk of torsades de pointes and fatal arrhythmias (43).
Does body posture affect the efficacy of baclofen? Due to the strain of abdominal organs, the LES pressure is significantly higher in the supine position than the upright position and a low basal pressure of the LES is one of the important mechanisms of the GERD (44). Theoretically, baclofen, which increases the pressure of the LES, will be more effective in upright reflux; because of the lower LES pressure in this posture. Two studies evaluated the effect and reported that baclofen significantly decreased reflux episodes only in the upright position (15,25). Thus, it seems that baclofen is not a good choice in patients with reflux in supine position (e.g., patients with nocturnal reflux). In contrast, Orr et al. (30) evaluated the efficacy of baclofen in reducing reflux during sleep (supine position). They reported that baclofen can not only significantly reduce reflux events during sleep, but also improve objective and subjective measures of sleep (30). So, it seems that the knowledge about the efficacy of baclofen in upright and supine positions are still paradoxical and more studies are needed to provide an answer.
Adding baclofen or suggesting anti-reflux surgery? After inadequate response from PPIs, the management of GERD is complex (45). Spechler et al. (46) compared the efficacy of medical treatment versus surgical treatment for refractory heartburn. 25 patients received baclofen plus omeprazole and 27 patients underwent nissen fundoplication surgery. The treatment success rate with surgery was significantly higher than medical treatment (67% against 28%, p-value = 0.007). Although the study evaluated heartburn (which is not specific for GERD, and also is not the only symptom of GERD), baclofen appears to be a less effective alternative for surgery candidates (46).

Other considerations
Baclofen may be more effective in some populations when other comorbidities of patients with GERD are considered. In addition to patients with muscle spasms, baclofen can be a priority in GERD patients with the following disorders:

Alcohol use disorder (AUD)
Alcohol is one of the substances that can relax the LES and exacerbates reflux symptoms. Patients with symptomatic GERD are frequently advised to abstain from alcohol (47). Moreover, studies have shown that 30-80 mg of baclofen per day could be effective in quitting alcohol or preventing relapse: an off-label indication (48). In symptomatic GERD patients with AUD, baclofen not only reduces symptoms by decreasing TLESR episodes but also aids in alcohol cessation as a lifestyle modification.

Non-acid reflux and rumination syndrome
Antacid medications (including histamine-2 blockers and PPIs) are the first-line treatment for GERD. However, in patients with non-acid reflux or rumination syndrome, the antacid approach does not relieve symptoms. In these patients, increasing LES pressure and minimizing TLESR episodes may be the best option (49, 50). Thus, if pH monitoring reveals non-acid reflux, baclofen could be the treatment of choice.

Obesity
Studies have shown that central obesity is associated with symptomatic GERD. The mechanism is thought to be associated with increasing the gastroesophageal pressure gradient and shortening of the lower esophageal sphincter, which baclofen can resolve the latter. Moreover, obese patients are at higher risk of long-standing GERD complications, including erosive esophagitis, Barrett esophagus, and esophageal adenocarcinoma (51). A pilot study shows the positive effects of baclofen on weight reduction in obese patients (52). Thus, in obese GERD patients, baclofen could reduce both the GERD symptoms and body weight, which is one of the risk factors for symptomatic GERD.

Finally, when and how?
Management of refractory GERD can be very challenging. In PPI non-responders, the American College of Gastroenterology recommends against adding medications other than PPI to the regiment (53); Sometimes it is inevitably necessary to add other medications. Although trials confirm the efficacy of baclofen as a stand-alone treatment for GERD, we do not recommend it as a mono-therapy. In PPI-resistant patients, a trial of adding baclofen to the PPI may be helpful under special circumstances. This can help reduce symptoms (regurgitation, heartburn, and belching) and may decrease the dose of PPI. We recommend against using baclofen in patients with extra-esophageal reflux symptoms (e.g., GERC); as the efficacy of baclofen is low and the side effects are more frequent and severe. Also, we recommend against using baclofen for maintenance therapy or long-term use. In patients with symptomatic reflux who are candidates for anti-reflux surgery but refuse, baclofen can be a modest alternative. However, these patients may experience more side effects of baclofen as well. To reduce side effects, starting baclofen with a dose of 5-10 mg and incrementing to a maximum dose of 60 mg is recommended. Symptomatic GERD patients (especially those with belching or upright reflux) with an AUD, non-acid reflux, or obesity may benefit more from baclofen. An esophageal manometry (measures LES pressure and length) can help selecting refractory GERD patients who may respond appropriately to baclofen. Suggested algorithm for administration of baclofen for refractory reflux disease is illustrated in Figure 2.

Limitations
Some limitations of this study should be taken into consideration. First, most of the studies diagnosed GERD (before and after intervention) by symptoms (not pH-monitoring) what is uncertain. Second, the relatively small number of trials in some outcome categories. This may diminish the persuasiveness of the conclusions. Third, the potential influence of the preexisting conditions and the severity of the reflux disease could not be investigated because of the limited information obtained from the reviewed articles. Fourth, as with any systematic review, limitations associated with potential publication bias should be considered. Furthermore, trials' variability, different patients' characteristics, and a wide range of outcome measures were other limitations.

Conclusion
The present study, to the best of our knowledge, is the first study that systematically addresses various aspects of baclofen administration in the spectrum of GERD patients. A trial of adding baclofen to the PPI may be helpful in PPI-resistant patients. Baclofen therapies may be more beneficial for symptomatic GERD patients who suffer AUD, non-acid reflux, or obesity. To reduce the side effects, we recommend starting baclofen with a low dose and increasing it gradually, avoiding prescribing more than 60 mg of baclofen per day, and paying close attention to the patients' history.

Data availability statement
The original contributions presented in this study are included in this article/Supplementary material, further inquiries can be directed to the corresponding authors.